There isn’t a home in Israel and very few in the Western world that doesn’t have a stock of paracetamol (commercially known here as Acamol and in other countries as Tylenol or Panadol) in their medicine cabinet to treat mild-to-moderate pain and fever.
Amazingly, until now, drug researchers have not understood how the common analgesic drug relieves pain.
A new study from the Hebrew University in Jerusalem (HUJI) reveals that paracetamol doesn’t function only in the brain; it also blocks pain at its source by acting on nerve endings in the body.
It is taken for muscle aches, toothaches, minor arthritis, pain, and aches caused by colds, flu, sprains, and menstrual discomfort.
The researchers worked with mice and rats whose bodies function in this aspect just like humans. When it is swallowed, the drug is metabolized in the liver.
Working for almost four years on the project, Prof. Alexander Binshtok from HUJI’s Faculty of Medicine and Center for Brain Sciences (ELSC) and Prof. Avi Priel from its School of Pharmacy identified a previously unknown peripheral mechanism.
Paracetamol’s active metabolite, called AM404, shuts down specific sodium channels in pain-sensing neurons, stopping pain signals before they reach the brain.
Binshtok and Priel said their discovery not only reshapes our understanding of how one of the world’s most common painkillers works but also opens the door to developing safer, more targeted pain treatments.
The researchers just published their findings in the prestigious journal PNAS (Proceedings of the National Academy of Sciences USA) under the title “The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels.”
The history and science behind paracetamol
Paracetamol was first synthesized in an unstable and impure form in 1852 by French chemist Charles Gerhardt in the 1850s and in its current form in 1878 by American chemist Harmon Northrop Morse.
Binshtok told The Jerusalem Post that serendipity played a role in the discovery of paracetamol: researchers had tried to treat a patient’s intestinal worms and asked pharmacists to make a drug for it.
That medication was ineffective against worms, but the patient did feel less pain. A century later, paracetamol was approved by the US Food and Drug Administration (FDA).
“We are studying molecular and cellular mechanisms of normal and chronic pain at all levels, starting from the terminal endings of peripheral neurons at the target organs and all the way up to the cerebral cortex.
“We are also developing new approaches for pain-selective anesthesia – an effective pain treatment without side effects,” Binshtok said.
FOR MANY years, scientists believed that paracetamol – an over-the-counter medication – relieved pain by working only in the brain and spinal cord, but their new study shows that the drug also works outside the brain, in the nerves that first detect pain.
The body’s primary sensor neurons create AM404 after the person takes paracetamol. The metabolite is produced right in the pain-sensing nerve endings and works by shutting off specific sodium channels that help transmit pain signals.
By blocking these channels, AM404 stops the pain message even before it starts.
“This is the first time we’ve shown that AM404 works directly on the nerves outside the brain,” said Binshtok.
“It changes our entire understanding of how paracetamol fights pain. This breakthrough could also lead to new types of painkillers. Because AM404 targets only the nerves that carry pain, it may avoid the numbness, muscle weakness, and side effects that come with traditional local anesthetics.”
The risk of Paracetamol poisoning
The recommended maximum daily dose of paracetamol for an adult is three to four grams. It can take up to an hour to work. The usual dose is one or two 500 mg. tablets at a time, up to four times in 24 hours. The maximum dose is eight 500 mg. tablets in 24 hours.
One must not take paracetamol with other medicines containing paracetamol because there is a risk of overdose and serious harm to the liver. Chronic consumption of paracetamol can spur a decline in hemoglobin level, indicating possible gastrointestinal bleeding and abnormal liver function tests.
Paracetamol poisoning is the most significant cause of acute liver failure in the Western world and accounts for most drug overdoses in the US, the United Kingdom, Australia, and New Zealand.
People must read the printed instructions that come with it before taking paracetamol, said Binshtok.
He continued: “It will take a few years to make a new drug based on AM404, and then it must earn FDA approval. I’m not a pharmacologist, but we hope Prof. Priel will continue working towards this goal. We at the medical faculty will continue to study other effects, including whether there are any on high fever.”
“If we can develop new drugs based on AM404, we might finally have pain treatments that are highly effective but also safer and more precise,” Priel said.
Binshtok received his doctoral degree from the HUJI in 2006, winning the highest honors. His graduate work focused on the cellular and molecular characteristics of neurons composing the rodent barrel cortex and their synaptic connectivity.
Before establishing an independent laboratory at HUJI in 2011, he served as an anesthesia instructor at Harvard Medical School, where he focused on the molecular and cellular mechanisms of normal and abnormal (chronic) pain, from the terminal endings of peripheral neurons to the properties of pain-related spinal cord circuitry and higher brain centers.
His lab takes a multidisciplinary approach to understanding the complex phenomenon of pain, using advanced genetic, molecular, electro-optical, and computational methods to study the plasticity of pain-related circuits along the entire neural pathway through which pain signals travel, from the periphery to the brain.
He and his team are also developing new approaches for pain-selective anesthesia – an effective pain treatment without side effects.
Many people, scientists, and drug companies contacted the HUJI team. “There were very interesting ideas on how we can continue. It’s a great adventure,” Binshtok concluded.